Objective To observe the effects of histone deacetylases inhibitor (HDACi) on cognitive performance and cerebral tau phosphorylation in transgenic mice coexpressed five familial Alzheimer' s disease mutations (5XFAD).Method The total 12 5XFAD-CC and 12 wild type (WT) mice were administrated with suberoylanilide hydroxamic acid ( SAHA,n =7) and vehicle ( n =5 ),respectively.The cognitive performance was assessed by Y-maze and Morris water maze.The protein levels of acetylated α-tubulin,total tau and phosphorylated tau and phosphorylated glycogen synthase kinase-3β (GSK3β) were determined by Western blotting.Results SAHA ameliorated learning and memory deficits in 5XFAD-CC mice (39.10％ ±2.25％,t =2.688,P =0.0312 for total numbers of entrance in novel arm; 26.81％ ±0.78％,t =3.271,P =0.017 for time spending in novel arm; F =5.936,P =0.045 for hidden platform;31.70％ ±4.21％,t =2.317,P =0.049 for probe trial).Administration of SAHA significantly increased acetylated α-tubulin in hippocampus of WT and 5XFAD-CC mice (26.42％ and 29.64％,respectively).Additionally,SAHA attenuated tau-pSer396,tau-pSer404 and tau-pThrThr231 in hippocampus of 5XFAD-CC mice (24.22％,48.98％ and 26.95％,respectively). Moreover,hippocampal phosphorylated GSK3β was markedly reduced in SAHA-treated 5XFAD-CC mice (31.29％). Conclusion SAHA may improve cognitive performance in 5XFAD-CC mice, which is associated with its significant effects on the phosphorylation of tau and GSK3β.

Objective To explore whether ginsenoside Rg1 can attenuate ?-amyloid peptide 25-35-induced Tau hyperphosporylation in rat embryo cortical neurons by regulating the activity of GSK-3? and PP2A. Methods Primary cultures of cortical neurons were prepared from the embryonic day 18?2 in Sprague-Dawley rats. The experimental groups were designed as follows:1.Neurons culture (control group); 2. Neurons exposed to 20?mol/L A?_ 25-35 for 12 hours (A?-model group); 3.Neurons exposed to 20?mol/L A?_ 25-35 and 10 mmol/L lithium chloride (LiCl), a specific inhibitor of glycogen synthase kinase-3?(GSK-3?), for 12 hours (LiCl group); 4.Neurons exposed to 20?mol/L A?_ 25-35 for 12 hours in the presence of 24-hour pretreatment with ginsenoside Rg1 (Rg1 pretreatment group) . Western blotting and immunocytochemical staining were used to detect the levels of Tau phosphorylation,total Tau and GSK-3? in cortical neurons. Non-radioimmunoassay was introduced to detect the activity of protein phosphatase 2A (PP2A). Results In A?-model group, the levels of Tau protein phosphorylation in the sites of Ser 396 ,Ser 199/202 ,Thr 231 and total Tau were enhanced. Meanwhile, the expression of GSK-3? was also increased, but the activity of PP2A was unchanged. In LiCl group and Rg1 pretreatment group , the hyperposphorylations of Tau protein and total Tau and the expression of GSK-3? were markedly reduced compared to those of the A?-model group (P

Objective To evaluate the effect of hydromorphone postconditioning on the electrophysiological stability during ischemia-reperfusion (I/R) in isolated rat hearts.Methods Healthy adult male Sprague-Dawley rats,aged 2-3 months,weighing 280-360 g,were heparinized and anesthetized with pentobarbital sodium.Their hearts were excised and perfused in a Langendorff apparatus with K-H solution saturated with 95％ O2-5％ CO2 at 37 ℃.Twenty-four Langendorff-perfused hearts were divided into 3 groups (n =8 each) using a random number table:control group (group C),I/R group and hydromorphone postconditioning group (group HM).The isolated hearts were subjected to 60 min ischemia followed by 60 min reperfusion to establish the model of isolated heart I/R injury.The isolated hearts were perfused with K-H solution containing 4.1 ng/ml hydromorphone for 10 min starting from onset of reperfusion in group HM.Heart rate,electrocardiogram,coronary flow,and monophasic action potential amplitude,in the left ventricular endocardium,mid-myocardium and epicardium the maximal increase rate (Vmax) at the 0 phase,and monophasic action potential duration at 50％ and 90％ repolarization (MAPD50 and MAPD90,respectively) were recorded at 20 min of stabilization (T0) and 10,25,40 and 60 min of reperfusion (T1-4).The transmural dispersion of repolarization (TDR) was calculated,and the time for restoratiou of spontaneous heart beat was recorded.Results There was no significant difference in the heart rate,coronary flow or monophasic action potential amplitude between the three groups (P＞0.05).Compared with group C,V in the epieardium was significantly decreased,MAPD50 and MAPD90 in the three transmural layers were prolonged,and TDR was prolonged in group I/R (P＜0.05).Compared with group I/R,the time for restoration of spontaneous heart beat,MAPD50 in the endoeardium and mid-myocardium,and MAPD90 and TDR in the endocardium were significantly shortened (P＜0.05),and no significant change was found in V in group HM (P＞0.05).Conclusion Hydromorphone postconditioning is helpful in maintaining the electrophysiological stability during I/R in isolated rat hearts.

Objective To evaluate the role of δ-opioid receptors in hydromorphone postcondition-ing-induced maintenance of electrophysiological stability during ischemia-reperfusion(I∕R)in isolated rat hearts. Methods Healthy male Sprague-Dawley rats, aged 2-3 months, weighing 280-360 g, were used in this study. The animals were anesthetized with intraperitoneal pentobarbital 60 mg∕kg. Their hearts were immediately removed and perfused in a Langendorff apparatus. Thirty-two isolated hearts were divided into 4 groups after successful preparation of Langendorff perfusion model(n=8 each)using a random number ta-ble: control group(group C), group I∕R, hydromorphone postconditioning group(group HP)and hydro-morphone plus δ-opioid receptor antagonist naltridole postconditioning group(group HNP). In HP and HNP groups, the hearts were perfused for 10 min with K-H solution containing 41 ng∕ml hydromorphone and 41 ng∕ml hydromorphone plus 5 μmol∕L naltridole, respectively, and then with K-H solution for 50 min. At 20 min of stabilization(T0)and 10, 25 and 60 min of reperfusion(T1-2), heart rate(HR), monophasic action potential(MAP)duration at 90% repolarization(MAPD90)of the two layers(endocar-dium, epicardium)of the anterior left ventricular wall were recorded. Transmural dispersion of repolariza-tion(TDR)was calculated. The development of arrhythmia, time for restoration of spontaneous heart beat and duration of arrhythmia were recorded during the period of reperfusion. Results Compared with group C, MAPD90of endocardium at T1-2and MAPD90of epicardium at T1were significantly prolonged in I∕R and HP groups, HR was significantly decreased at T2-3, MAPD90of endocardium and epicardium was prolonged at T1-3in group HNP, TDR was significantly enlarged at T1in group I∕R and at T2in group HNP, and TDR was decreased at T3in group HP(P<005). Compared with group I∕R, no significant change was found in arrhythmia score(P>005), the time for restoration of spontaneous heart beat was significantly shortened, and TDR was decreased at T1in HP and HNP groups, duration of arrhythmia was significantly shortened, and MAPD90of endocardium was shortened at T1in group HP, and HR was significantly decreased at T2-3, MAPD90of endocardium and epicardium was prolonged at T1-3, and TDR was decreased at T2-3in group HNP(P<005). Compared with group HP, no significant change was found in time for restoration of spon-taneous heart beat, duration of arrhythmia or arrhythmia score(P>005), HR was significantly decreased at T2-3, MAPD90of endocardium and epicardium was prolonged at T1-3, and TDR was increased at T3in group HNP(P<005). Conclusion The mechanism underlying hydromorphone postconditioning-induced maintenance of electrophysiological stability during I∕R is related to activating δ-opioid receptors in isolated rat hearts.

Objective To investigates the effect of acupuncture on sensitization of Zusanli(ST36)in rats with different functional states by using healthy and knee osteoarthritis model rats.Methods Male SD rats were randomly divided into control,model,model-acupuncture and blank-acupuncture group,with 7 rats in each group.KOA rat model was prepared by intra-articular injection of 1 mg·50 μL-1 monoiodoacetic aci(MIA)in model group and model-acupuncture group.On the second day of modeling,acupuncture treatment was performed on the left Zusanli of the model acupuncture group and the blank-acupuncture group,once everyday for 20 min,5 times as a course of treatment,2 days between courses.The general condition,knee joint diameter,plantar thermal pain threshold and Lequesne MG score of rats was observed before modeling and after acupuncture.Observing the morphology of knee joint cartilage to judge whether the model is successful,measuring the mechanical pain threshold of Zusanli to investigate the acupoint sensitization,observing and counting the morphology of skin mast cells in the acupoint area,and detecting the expression of skin calcitonin gene-related peptide(CGRP)in the acupoint area.Results The mechanical pain threshold of Zusanli after acupuncture in model group and blank-acupuncture group decreased significantly after modeling(P<0.01,P<0.05),compared with the control group,the change rate of mechanical pain threshold in model group and blank-acupuncture group increased significantly(P<0.05),compared with the model group,the mechanical pain threshold of Zusanli in the model-acupuncture group decreased significantly(P<0.01).Compared with the control group,the fluorescence intensity of CGRP protein in the skin tissue of Zusanli in the model group increased significantly(P<0.01),MC degranulation rate increased significantly(P<0.05),and there was no significant difference in the fluorescence intensity of CGRP protein of Zusanli in the blank-acupuncture group(P>0.05),MC degranulation rate increased obviously(P<0.01),CGRP protein of Zusanli in the model-acupuncture group was significantly reduced compared with the model group(P<0.01),and there was no significant difference in the degranulation rate of MC(P>0.05).Conclusion Acupoint sensitization can occur in different functional states of rats.Zusanli(ST36)of KOA model rats can be sensitized,and acupuncture stimulation can make Zusanli sensitization caused by disease disappear.Under physiological conditions,acupuncture stimulation can induce similar sensitization phenomenon.

Objective:To analyze the modifiable risk factors for early-onset Alzheimer's disease (EOAD), and provide evidence for primary prevention of EOAD.Methods:Forty patients with EOAD, admitted to our hospital from January 2015 to April 2020, were selected as EOAD group, and 120 healthy controls accepted physical examination and matched with EOAD patients in age, gender and education level were selected. Demographic characteristics and clinical data of patients from the EOAD group and subjects from the control group were compared retrospectively, and multivariate Logistic regression was used to analyze the independent risk factors for onset of EOAD.Results:As compared with the control group, the EOAD group had significantly higher proportion of patients with hypertension, non-traumatic tooth loosening or loss, history of traumatic brain injury, hearing impairment, chronic stress and/or anxiety, and sleep disorder ( P<0.05). The results of multivariate Logistic regression analysis showed that hypertension ( OR=4.559, 95%CI=1.523-13.643, P=0.007), non-traumatic loss or loosing of tooth ( OR=5.345, 95%CI=1.989-14.346, P=0.001), hearing impairment ( OR=9.336, 95%CI=2.033-27.850, P=0.000), chronic stress and/or anxiety ( OR=7.375, 95%CI=2.612-20.822, P=0.000), and sleep disorder ( OR=4.875, 95%CI=1.520-15.625, P=0.002) were independent risk factors for onset of EOAD. Conclusion:Hypertension, non-traumatic loss or loosing of tooth, hearing impairment, chronic stress and/or anxiety, and sleep disorders are risk factors for onset of EOAD; the screening and intervention of these risk factors can be used as a primary prevention strategy for EOAD.

Dyskeratosis congenita (DC) is a rare disease and a genetic heterogeneity of bone marrow failure, characterized by muco-cutaneous triad of mucosal leukoplakia, abnormal skin pigmentation, nails dystrophy and often involving multiple organs or systems. The inheritance patterns of DC include X-linked recessive, autosomal dominant and recessive patterns. However, the inheritance patterns in 30%-40% of DC patients remained unknown. Dyskeratosis congenita is difficult to diagnose because of its genetic and clinical heterogeneity. This article will review and discuss the state-of-the-art progresses in genetics, clinical manifestation, diagnosis, differential diagnosis, treatment and prognosis of DC.

OBJECTIVE:To establish a method for the determination of dendrobine and its metabolites M-250 and M-280 in mice plasma for the first time. METHODS:Mice were given dendrobine 60 mg/kg by intragastric administration,1 h later plasma were collected and treated. Using pseudoephedrine hydrochloride as internal standard and dendrobine reference substance as control, the plasma concentrations of dendrobine and its metabolites M-250 and M-280 were determined by UPLC-MS combined with quantitative analysis of multi-components by single marker. The separation was performed on Hypersil Gold C18 column with 0.1％formic acid-acetonitrile(gradient elution)at the flow rate of 0.3 mL/min. The column temperature was set at 40℃,and sample size was 5 μL. Heatable electrospray ionization (HESI) source, scan/ESI + were applied and operated in positive ion mode with atomization temperature of 300℃,ion transmission tube temperature of 350℃,the sheath gas velocity of 35 arb,the auxiliary air velocity of 15 arb,the spray voltage of 3.5 kV,the collision voltage of 30,40,50 eV. The mass-to-charge ratio of detection range were 100-1500. RESULTS:The endogenous substances of mice plasma had no interference with the content determination of dendrobine and its metabolites M-250 and M-280. The linear range of dendrobine were 9.13-912.94 ng/mL(r=0.9996). The limit of quantitation was 3.04 ng/mL. RSDs of intra-day and inter-day were all less than 7.5％(n=5 or n=3). The accuracy were 96.8％-107.5％(n=5). Matrix effects were 97.1％-106.0％(RSD=1.8％-4.7％,n=5). RSDs of the content of sample at 15℃ for 24 h,at -70 ℃ after three times freeze-thaw,at -70 ℃ for 15 d were lower than 12.8％ (n=3). The content of dendrobine in plasma sample of mice was (41.3 ± 5.7) ng/mL (n=12). The contents of its metabolites M-250 and M-280 were (493.0 ± 73.1) and (41.4 ± 3.0) ng/mL (n=12) with Relative correction factor of 1.0. CONCLUSIONS: The method is sensitive and accurate,and can be used for content determination of dendrobine and its metabolites M-250 and M-280 in mice plasma.

In recent years, the clinical guidelines for the diagnosis and treatment of rheumatoid arthritis (RA) have been constantly updated. Among the general principles, it is particularly emphasized that, in order to improve the ratio of treat to target(T2T) of RA, doctors and patients should work together to negotiate the details of the guidelines. Therefore, it is important for patients to further understand the disease and clinical guidelines of RA, and to better cooperate with doctors. This study was based on the most concerned issues of RA patients and international standard procedure of guideline study, we organized the working group and introduce the following 16 recommendations constituting the RA patients′ practice guidelines.

In recent years, osteoporosis (OP) has become one of the main diseases affecting the health of middle-aged and elderly people in China, and the prevalence of OP has increased significantly. The clinical diagnosis and treatment guidelines for this disease are also constantly updated. The overall principles speciallyemphasise that doctors and patients need to work together to negotiate the details of the diagnosis and treatment guidelines, in order to improve the OP clinical diagnosis and treatment rate. Therefore, patients′ knowledge of the disease, understanding of clinical guidelines, and cooperation with doctors to implement diagnosis and treatment plans are very important. In this study, from the most concerned issues of the patients, we established the OP patient practice guideline working group. 14 recommendations, as the OP patient practice guidelines, are proposed in accordance with the relevant principles of the "World Health Organization guidelines development manual" and the international normative process.